Hypertriglyceridemia is a disease state in which there is an excessive amount of triglyceride in the plasma. Hypertriglyceridemia can lead to various undesirable effects. For example, hypertriglyceridemia can cause increases in concentrations of certain abnormal lipoproteins which may play a role in atherogenesis and the development of coronary heart disease. In addition, hypertriglyceridemia is known to be a cause of acute pancreatitis which can be a life-threatening condition. It is therefore desirable to provide a method for reducing plasma triglycerides in patients with hypertriglyceridemia.
Triglycerides in the diet are hydrolyzed in the intestine to monoglycerides and fatty acids. These hydrolysis products are absorbed by the intestinal mucosa where they are resynthesized into triglycerides. These triglycerides are then incorporated into lipoproteins called chylomicrons which contain cholesterol, phospholipid and triglycerides in addition to a protein component. The triglyceride-rich chylomicrons are secreted into the blood stream via the lymph system. Circulating chylomicrons are exposed to the enzyme lipoprotein lipase which catalyzes the hydrolysis of chylomicron triglycerides to free fatty acids. After the removal of most of the triglycerides, the chylomicron remnant, which is now cholesterol-rich, is further removed from the blood stream by the liver.
In addition, the liver secretes into the blood stream endogenous triglyceride-rich lipoproteins called very low density lipoproteins (VLDL). As the VLDL circulates, a portion of the VLDL-associated triglycerides is removed by lipolysis catalyzed by lipoprotein lipase and hepatic triglyceride lipase. At the same time, the circulating VLDL pick up cholesterol ester from other circulating lipoproteins such as high density lipoproteins (HDL). Circulating VLDL continue to undergo these modifications leading to progressively smaller particles which are depleted in triglycerides and enriched in cholesterol ester. The triglyceride-depleted VLDL are cleared by the liver or are degraded further to another form of lipoprotein called low density lipoprotein (LDL). Although LDL normally carry relatively small amounts of triglycerides and do not play a major role in triglyceride transport in the blood, various epidemiologic studies have indicated that LDL cholesterol levels correlate well with the risk of coronary heart disease [Patton et al., Clin. Chem. 29, 1890 (1983)]. It is generally accepted by those skilled in the art that reduction of abnormally high LDL cholesterol levels is effective therapy in the treatment of atherosclerosis.
The presence of hypertriglyceridemia in a patient can cause abnormalities in all of the circulating lipoproteins. Endogenous hypertriglyceridemia causes prolonged chylomicronemia and increases in partially catabolized chylomicron remnants following fat ingestion. Hypertriglyceridemia is also associated with a prolonged residence time of VLDL in the circulation and gives rise to several changes in VLDL composition. These modified VLDL are more readily taken up by macrophages to form fatty foam cells which eventually lead to the formation of atherosclerosis. Various compositional changes in LDL and HDL also occur as a result of hypertriglyceridemia leading to abnormal LDL and HDL.
Although the presence of hypertriglyceridemia may not be atherogenic per se, since triglycerides do not themselves accumulate in atherosclerotic plaque and elevated plasma triglyceride does not appear to be an independent risk factor for coronary heart disease in epidemiologic studies, hypertriglyceridemia can lead to the formation of certain abnormal circulating lipoproteins which may themselves be atherogenic [See Vega and Grundy, Adv. Exp. Med. Biol. 243, 311 (1989)]. Reduction of triglyceride levels in a patient suffering from hypertriglyceridemia can therefore provide the beneficial effect of reducing levels of certain abnormal atherogenic lipoproteins.
Acute pancreatitis is a process of autodigestion caused by the premature activation of zymogens to the corresponding active digestive enzymes within the pancreas. It is well accepted that elevated circulating triglyceride levels can trigger attacks of acute pancreatitis. It is further well accepted that recurrences of attacks of acute pancreatitis can be prevented by treatment aimed at lowering plasma triglyceride levels [See K. Soergel, ACUTE PANCREATITIS, in Gastrointestinal Disease 91, 3rd ed. (Sleisenger, M. H., and Fordtran, J. S., eds.), W. B. Saunders Company, Philadelphia, Pa., 1983, pp. 1462-1485; and See Brown, M. S., and Goldstein, J. L., DRUGS USED IN THE TREATMENT OF HYPERLIPOPROTEINEMIAS, in Goodman and Gillman's, The Pharmacological Basis of Therapeutics 34, 7th edition, (Macmillan Publishing Co., New York, 1985, pp. 827-845].
The present invention relates to the use of certain bis(3,5-di-alkyl-4-hydroxyphenylthio)methanes, such as bis(3,5-di-tertiarybutyl-4-hydroxyphenylthio)methane, in treating patients suffering from hypertriglyceridemia. Bis(3,5-di-tertiarybutyl-4-hydroxyphenylthio)methane is disclosed in U.S. Pat. No. 4,900,757 as providing a hypocholesterolemic and a antiatheroscleotic effect in patients treated therewith.